In this study, dual staining shows that with aging MCP-1 and TGF-beta1, a powerful profibrogenic cytokine, markedly increase and co-localize within the aortic wall in the thickened intima of rats, nonhuman primates, and humans. Cardiovascular signaling network analysis indicates that MCP-1 interacts with TGF-beta1 and is centrally located and directly connected with the inflammation cascade, which is closely associated with MMP-2 activation. In vitro study shows that MCP-1 elevates MMP2, a known activator of latent TGF-beta1 in a dose- or time-dependent manner through CCR-2 signaling in cultured vascular smooth muscle cells (VSMC) from young (8 mo) rat aortae, reaching the levels of old cells (30mo). MCP-1 treatment increases activated intracellular and extracellular TGF-beta1 and its downstream molecules collagen types I and III, which is dependent upon MMP-2 activation in young VSMC, reaching levels of untreated old cells. Furthermore, cellular activated TGF-beta1 is distributed and increased in VSMC sub-fractions, including cytosol, the organelles and the nuclei, with aging. Interestingly, knockdown of MCP-1 via siRNA or overexpression of ectopic TIMP-2 by adenovirus transfection reduces activation of MMP-2 and TGF-beta1 and production of invasive capacity of young cells in an MMP-2 activation-dependent manner, resembling that of untreated old cells. These effects are substantially reduced by both CCR-2 and an MMP inhibitor, GM 6001. Of note, TGF-beta1 treatment increases MCP-1, MMP-2, and VSMC invasiveness in a dose-dependent manner in young VSMC, up to levels of old untreated cells. Furthermore, we demonstrate that a novel protein, Vasorin, is markedly down-regulated in the aged arterial wall, which is closely associated with an increase of TGF-beta1 activity and arterial fibrosis. Further in vitro studies indicate that aging also upregulated TGF-beta1, SMAD 2 and collagen I expression within VSMC; Ang II treatment of young VSMC upregulated the levels of TGF-beta1, SMAD 2 and collagen I expression up to the same levels as from old cells; aging down-regulated Vasorin expression in old rat VSMC as compared with young; TGF-beta1 interacts with Vasorin in rat VSMC; aging affects the interaction of TGF-beta1 with Vasorin; overexpression of Vasorin counteracts TGF-beta1 signaling pathway and collagen I expression in VSMC from old rats; overexpression of Vasorin counteracts TGF-beta1 signaling pathway and collagen I expression induced by Ang II treatment in VSMC from young rats. Taken together, this complex local signaling loop of MCP-1/MMP-2/TGF-beta1 plays a bedrock role in the initiation and progression of age-associated arterial intimal cellularity and fibrosis. Interruption of this vicious cycle is a potential therapeutic approach to arterial health in the elderly.